灯盏乙素在多种细胞色素P450和尿苷二磷酸葡萄糖醛酸基转移酶作用下的体外代谢

In vitro metabolism of eupatilin by multiple cytochrome P450 and UDP-glucuronosyltransferase enzymes.

作者信息

Lee H S, Ji H Y, Park E J, Kim S Y

机构信息

Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy and Medicinal Resources Research Institute, Wonkwang University, Iksan, Korea.

出版信息

Xenobiotica. 2007 Aug;37(8):803-17. doi: 10.1080/00498250701534877.

DOI:10.1080/00498250701534877

PMID:17701830

Abstract

Eupatilin, a pharmacologically active flavone derived from Artemisia plants, is extensively metabolized to eupatilin glucuronide, 4-O-desmethyleupatilin and 4-O-desmethyleupatilin glucuronide in human liver microsomes. This study characterized the human liver cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes responsible for the metabolism of eupatilin. The specific CYPs responsible for O-demethylation of eupatilin to the major metabolite, 4-O-desmethyleupatilin were identified using a combination of correlation analysis, immuno-inhibition, chemical inhibition in human liver microsomes and metabolism by human cDNA-expressed CYP enzymes. UGT enzymes involved in the eupatilin glucuronidation were identified using pooled human liver microsomes and human cDNA-expressed UGT enzymes. Eupatilin was predominantly metabolized by CYP1A2 and, to a lesser extent, CYP2C8 mediated O-demethylation of eupatilin to 4-O-desmethyleupatilin. Eupatilin glucuronidation was catalysed by UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT1A10.

摘要

灯盏乙素是一种从蒿属植物中提取的具有药理活性的黄酮类化合物，在人肝微粒体中可广泛代谢为灯盏乙素葡萄糖醛酸苷、4-O-去甲基灯盏乙素和4-O-去甲基灯盏乙素葡萄糖醛酸苷。本研究对负责灯盏乙素代谢的人肝细胞色素P450（CYP）和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）进行了表征。通过相关性分析、免疫抑制、人肝微粒体中的化学抑制以及人cDNA表达的CYP酶代谢等方法相结合，确定了负责将灯盏乙素O-去甲基化为主要代谢产物4-O-去甲基灯盏乙素的特定CYP。使用人肝微粒体池和人cDNA表达的UGT酶确定了参与灯盏乙素葡萄糖醛酸化的UGT酶。灯盏乙素主要通过CYP1A2代谢，其次是CYP2C8介导灯盏乙素O-去甲基化为4-O-去甲基灯盏乙素。灯盏乙素葡萄糖醛酸化由UGT1A1、UGT1A3、UGT1A7、UGT1A8、UGT1A9和UGT1A10催化。